Amide bonds are ubiquitous in Nature and represent one of the most important functional groups that constitute biomolecules. Amides are the key units to the backbone of peptides and proteins, and are an important component of nucleotides. Consequently, the development of synthetic methods for amidation and peptide synthesis has long preoccupied chemists. Despite the favorable thermodynamic stability of the resulting amide bond, the simple dehydrative reaction between a free carboxylic acid and an amine is process plagued by a large activation energy. The initial formation of a stable ammonium carboxylate salt deters the dehydration step. The salt intermediate collapses to provide the amide product only at very high temperatures (typically over 160° C.) that are incompatible with functionalized molecules. Consequently, this important classical reaction continues to challenge chemists and there are still no means to make amides directly between free carboxylic acids and amines in a simple, green and atom-economical fashion.
Most current amide bond-forming methods involve the use of super-stoichiometric amounts (i.e., large excesses) of expensive and toxic reagents such as carbodiimides, carbonyldiimidazole, phosphonium salts, and others, to activate and dehydrate the carboxylic acid. These coupling agents and their associated co-reagents (bases, supernucleophiles, other additives) generate large amounts of wasteful by-products that tend to complicate the isolation of the desired amide.
The direct formation of amide bonds has been known since 1858 (Benz, G. In Comprehensive Organic Synthesis, Vol 6; Trost B. M., Fleming I., Heathcock C. H. Pergamon press: New York, 1991, Chap. 2.3). Catalysts that have been used for amidation reactions between carboxylic acids and amines include TiCl4 (Carlson et al. Acta Chem. Scand. Ser. B. 1988, 28), Ti(O-i-Pr)4, (Helquist et al. Tetrahedron Lett. 1988, 59, 3049), Ph3SbO/P4S10 (Matsuda et al. J. Org. Chem. 1991, 56, 4076), Sb(OEt)4 (Yamamoto et al. J. Am. Chem. Soc. 1996, 118, 1569) and ArB(OH)2 (Ishihara et al. J. Org. Chem. 1996, 61, 4196), however, an efficient catalytic procedure that functions mildly under ambient conditions (i.e., room temperature) has not yet been developed.
The ArB(OH)2 catalysts reported in Ishihara et al. (id) included those where Ar is 3,4,5-trifluorophenyl, 3-nitrophenyl, 3,5-di-(trifluoromethyl)phenyl, 4-trifluoromethylphenyl, phenyl, 2,4,6-tri-(trifluoromethyl)phenyl and 2,3,4,5-tetrafluorophenyl. The reactions were performed at temperatures of about 110° C. (refluxing toluene) with a catalyst loading of 5 mol % and with the removal of water using 4 Å molecular sieves in a Soxhlet thimble. A solid phase version of these catalysts was reported by Latta et al. (Synthesis. 2001, 11, 1611-1613) but it also requires very high temperatures.